Calcium sensor regulation of the Ca _V 2.1 Ca ²⁺ channel contributes to short-term synaptic plasticity in hippocampal neurons

Abstract

Short-term synaptic plasticity is induced by calcium (Ca 2+ ) accumulating in presynaptic nerve terminals during repetitive action potentials. Regulation of voltage-gated Ca V 2.1 Ca 2+ channels by Ca 2+ sensor proteins induces facilitation of Ca 2+ currents and synaptic facilitation in cultured neurons expressing exogenous Ca V 2.1 channels. However, it is unknown whether this mechanism contributes to facilitation in native synapses. We introduced the IM-AA mutation into the IQ-like motif (IM) of the Ca 2+ sensor binding site. This mutation does not alter voltage dependence or kinetics of Ca V 2.1 currents, or frequency or amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs); however, synaptic facilitation is completely blocked in excitatory glutamatergic synapses in hippocampal autaptic cultures. In acutely prepared hippocampal slices, frequency and amplitude of mEPSCs and amplitudes of evoked EPSCs are unaltered. In contrast, short-term synaptic facilitation in response to paired stimuli is reduced by ∼50%. In the presence of EGTA-AM to prevent global increases in free Ca 2+ , the IM-AA mutation completely blocks short-term synaptic facilitation, indicating that synaptic facilitation by brief, local increases in Ca 2+ is dependent upon regulation of Ca V 2.1 channels by Ca 2+ sensor proteins. In response to trains of action potentials, synaptic facilitation is reduced in IM-AA synapses in initial stimuli, consistent with results of paired-pulse experiments; however, synaptic depression is also delayed, resulting in sustained increases in amplitudes of later EPSCs during trains of 10 stimuli at 10-20 Hz. Evidently, regulation of Ca V 2.1 channels by CaS proteins is required for normal short-term plasticity and normal encoding of information in native hippocampal synapses.calcium channel | calcium sensor proteins | synaptic facilitation | calmodulin | hippocampus

Calcium sensor regulation of the Ca V 2.1 Ca 2+ channel contributes to long-term potentiation and spatial learning

“…Our previous studies of IM-AA mice showed that regulation of presynaptic Ca V 2.1 channels by CaS proteins contributes substantially to short-term synaptic plasticity in hippocampal synapses (21). In those studies, we found that the IM-AA mutation does not alter the frequency or amplitude of miniature EPSCs caused by presynaptic release of single quanta of glutamate or the amplitudes of EPSCs recorded in response to increasing presynaptic stimulus intensities.…”

“…In IM-AA synapses, the initial facilitation of EPSCs in response to a train of action potentials is reduced in amplitude, but facilitation eventually reaches a comparable level to WT and is sustained longer because the rapid phase of synaptic depression is slowed (21). Overall, the integral of EPSCs is actually increased during a train of stimuli (21). This persistent increase in EPSC amplitude during trains of stimuli in vivo may engage homeostatic regulatory mechanisms that weaken LTP, as we have reported here.…”

“…Multiple step depolarizations were given at the beginning of every experiment to induce block of Na 2+ and Ca 2+ currents in the CA1 pyramidal cells by QX-314 (21). LTP was induced in both WT and IM-AA in SC-CA1 synapses by eight trains of θ-burst stimulation (10 bursts delivered at 5 Hz, each burst consisting of 10 pulses at 100 Hz), while CA1 neurons were depolarized to −40 mV.…”

“…To further explore the role of Ca V 2.1 channel regulation by CaS proteins in spatial learning and memory, we used knockin mice with paired alanine substitutions for the isoleucine and methionine residues in the IQ-like motif (IM-AA) in their C-terminal domain (21), and we studied LTP and spatial learning and memory in IM-AA mice. In addition to the previously documented alterations in short-term facilitation in Schaffer collateral (SC)-CA1 synapses in acute hippocampal slices (21), we found major deficits in LTP and in spatial learning and memory, which reveal unexpected connections among presynaptic neuroplasticity, postsynaptic LTP, and spatial learning and memory.…”

Tissue-specific dynamin-1 deletion at the calyx of Held decreases short-term depression through a mechanism distinct from vesicle resupply

“…4 A and B). A relevant question is activity-dependent Ca 2+ current facilitation because it modulates neurotransmission even with undistinguishable Ca 2+ influx under basal conditions (51). We thus applied 30 AP-like (AP-L) pulses (1 ms, +30 mV, 333 Hz) to mimic afferent AP activity (Fig.…”